Yoo Jin Lee

Mobilization effects of G‐CSF, GM‐CSF, and darbepoetin‐α for allogeneic peripheral blood stem cell transplantation

The effects of GM‐/G‐CSF and darbepoetin‐α on stem cell mobilization were investigated. From February 2005 to March 2007, 30 allogeneic sibling donors were randomly assigned to a G‐CSF group (5 μg/kg/day for 5–7 days) or triple group (GM‐CSF 10 μg/kg/day on 1st and 2nd day, G‐CSF 5 μg/kg/day for 5–7 days, and darbepoetin‐α 40 mg on 1st day). The MNCs and CD34+ cells were not different between the two groups, although the doses (×108/kg of recipient body weight) of CD3+ cells (3.64 ± 1.75 vs. 2.63 ± 1.36, P = 0.089) and CD8+ cells (1.07 ± 0.53 vs. 0.60 ± 0.30, P = 0.006) were lower in the triple group. The engraftments, frequency of RBC transfusions, and hemoglobin recovery were not different between the two groups. The cumulative incidence of overall and Grades II–IV aGVHD was 64.3% vs. 61.1% and 25.9% vs. 27.1% in the G‐CSF and triple regimen group, respectively, whereas the cumulative incidence of cGVHD was 20.8 ± 1.3% and 24.4 ± 1.7%, respectively. In conclusion, the triple regimen did not seem to be superior to G‐CSF alone in terms of the CD34+ cell dose, hemoglobin recovery, and GVHD. However, the CD8+ cell count was significantly lower in the triple regimen group. The role of a lower CD8+ cell count in the graft may need to be elucidated in the future. J. Clin. Apheresis, 2009.

BCR-ABL translocation as a favorable prognostic factor in elderly patients with acute lymphoblastic leukemia in the era of potent tyrosine kinase inhibitors

The clinical outcome of acute lymphoblastic leukemia (ALL) depends strongly on the dose-intensity of chemotherapy delivered. The importance of dose-intensity resulted in the establishment of pediatric-inspired regimens for the treatment of fit adults with ALL. ALL patients with the BCR-ABL translocation, the so-called Philadelphia chromosome-positive ALL (Ph+ ALL), form a distinct subgroup, accounting for 20-30% of the adult ALL population. Although the BCR-ABL translocation is a well-known adverse prognostic factor in ALL, treatment of Ph+ ALL has improved dramatically with the advent of tyrosine kinase inhibitors (TKI) targeting ABL kinase. Imatinib, nilotinib, dasatinib, and ponatinib have all shown promising efficacy in terms of increased complete remission achievement and prolonged relapse-free survival and overall survival in Ph+ ALL. Allogeneic stem cell transplantation (ASCT) remains the recommended consolidative treatment for fit Ph+ ALL patients, but recent evidence suggests that newer ABL TKI are capable of long-term disease control without ASCT in certain Ph+ ALL populations. Some reports have even suggested the possibility of using these secondand thirdgeneration TKI as the sole consolidation modality without cytotoxic chemotherapy. Epidemiologically, patients over 60 years of age account for a significant proportion of ALL patients. These elderly patients are often unfit for either dose-intensive chemotherapy or ASCT and their clinical outcomes have, therefore, been dismal. The increased incidence of BCR-ABL translocation with older age also contributes to the poor prognosis of elderly ALL patients. However, we conjectured that, with the introduction of potent TKI targeting ABL, the BCR-ABL translocation might not have a negative prognostic impact in elderly ALL. Considering that many elderly PhALL patients do not tolerate the cytotoxic chemotherapy required for effective tumor control, we supposed that the efficacy of ABL TKI and their combination with lowdose cytotoxic chemotherapy would result in better survival for elderly Ph+ ALL patients compared to their Phcounterparts. Through our study we confirmed our hypothesis and found that Ph chromosome positivity may actually be a better prognostic factor in elderly patients in the era of potent TKI. This study was a multicenter, retrospective, longitudinal cohort study of elderly patients (≥60 years) with de novo ALL recruited from 13 hospitals in Korea between January 2006 and December 2015. Overall 114 patients were identified and after exclusion of 11 with incomplete data, 103 cases were finally evaluated. Five patients in the Ph+ group did not receive a TKI (1 due to poor oral intake, 1 due to the patient’s refusal and 3 for unknown reasons), and they were excluded from the analyses. This study was conducted according to the Declaration of Helsinki and was approved by the institutional review boards of all the participating hospitals. We considered a patient to have Ph+ ALL if the translocation was found by at least one of three techniques: conventional cytogenetics, fluorescence in situ hybridization, or quantitative real-time polymerase chain reaction. Differences between groups were assessed using the Student t-test or one-way analysis of variance for continuous variables, and the Pearson chi-square test for categorical variables, as indicated. Complete remission was defined as less than 5% blasts in bone marrow, while relapse was defined by recurrence of a bone marrow blast count above 5% or extramedullary disease after a previously documented complete remission. The overall and relapse-free survival curves were estimated using the Kaplan-Meier method. Overall survival was defined as the time from ALL diagnosis to death, and relapse-free survival as the time from ALL diagnosis to relapse or death. If patients survived without progression, survival was censored on the latest date of follow-up. If the patient underwent ASCT, overall and relapse-free survival were censored at the time of transplantation. Univariate and multivariate proportional hazards regression models were used to identify independent risk factors for relapse-free survival and overall survival. Factors associated with ALL prognosis, including age, white blood cell count at diagnosis, Philadelphia chromosome status, ALL subtype, and induction regimen were included in multivariate analyses. All data were analyzed using the Statistical Package for the Social Sciences software (IBM® SPSS®Statistics, version 22.0). Of the 98 patients analyzed, 51 (52.0%) had PhALL and 47 (48.0%) had Ph+ ALL. There were no differences between the two groups with regards to age, sex distribution, performance status, and induction regimens (Table 1). Ph+ ALL patients had higher peripheral and bone marrow blast counts at diagnosis. MLL rearrangement status was available for 37 (72.5%) of the PhALL patients, and four (10.8%) were positive for the genetic

Clinical impact of induction treatment modalities and optimal timing of radiotherapy for the treatment of limited-stage NK/T cell lymphoma

This study retrospectively investigated the optimal timing of radiotherapy (RT) in patients with limited-stage extranodal NK/T-cell lymphoma (ENTKL). Among 158 patients with newly diagnosed stage I/II ENKTL, 61 patients were treated with sequential chemotherapy followed by radiotherapy (SCRT), 55 with concurrent chemoradiotherapy followed by non-anthracycline-based chemotherapy (CCRT/CT), and 42 with chemotherapy (CT) only. The 5-year overall survival (OS) rate did not differ between SCRT (77.7±5.5%) and CCRT/CT (68.9±6.8%; p=0.234). In the SCRT group, 18 patients (29.5%) relapsed within the RT field and 6 (9.8%) at systemic sites, while in the CCRT/CT group, 9 patients (16.4%) relapsed at the primary site and 14 (25.5%) at systemic sites. The 5-year cumulative incidence of relapse (CIR) at primary sites was 26.3% and 19.2% after SCRT and CCRT/CT (p=0.308), while the 5-year CIR of systemic sites was 8.7% and 26.5% after SCRT and CCRT/CT, respectively (p=0.010). In the multivariate analysis, NK/T-cell Prognostic Index score and CR achievement were the most important prognostic factors for survival. Although up-front RT had limitations in systemic disease control and was associated with an increased risk of systemic relapse during RT compared to SCRT, timing of RT did not significantly affect survival outcomes.

Survey of experts on therapeutic policies and proposals for the optimal timing for allogeneic peripheral blood stem cell transplantation in transfusion-dependent patients with myelodysplastic syndrome-refractory anemia

Background Most hypomethylating agent (HMA) responders with myelodysplastic syndrome (MDS) eventually need allogeneic stem cell transplantation (SCT) because they often acquire resistance to HMAs within two years of treatment. Considering the nature of MDS and the poor outcomes of SCT when performed after confirming the progression of MDS to acute myeloid leukemia (AML), allogeneic SCT should be performed with caution in patients with low-risk MDS. Methods To address low-risk MDS, the Korean AML/MDS working party group designed a survey for 34 MDS experts in Korea on therapeutic HMA and allogeneic SCT policies for low-risk MDS. The level of consensus was defined as the percentage of agreement among the experts. Results With regard to the optimal time for allogeneic SCT for HMA responders with MDS-RA, 76% experts agreed that allogeneic SCT should be performed when a patient has a low platelet count. With regard to the relapse pattern that was most commonly found during HMA treatment in responding patients with MDS-RA, 54% experts agreed that the most common pattern that indicated HMA failure was the gradual worsening of cytopenia. Conclusion The optimal time to perform allogeneic SCT in RA patients who achieved hematologic complete remission during HMA treatment is when the platelet count decreases. However, these suggestions need to be evaluated in larger future studies. Therefore, careful decisions should be taken at each step of allogeneic SCT to maximize the outcomes for patients with MDS-RA and iron overload.

Chemotherapy adherence is a favorable prognostic factor for elderly patients with multiple myeloma who are treated with a frontline bortezomib-containing regimen

Background Elderly patients with multiple myeloma (MM) are vulnerable to adverse events (AEs). This study evaluated adherence to chemotherapy and treatment outcomes in elderly patients treated with a frontline bortezomib (BTZ), melphalan, and prednisone (VMP) regimen and regimens without BTZ. Methods One-hundred and forty elderly patients who were diagnosed with MM from March 2007 to March 2015 were included in this retrospective study. To evaluate regimen adherence, patients who were treated with more than 4 cycles were assigned to the good adherence group. Results Among the 140 patients, 71 were treated with a frontline VMP and 69 with non-BTZ regimens. The median age was 71 years (range, 65-90 years). The VMP group showed a higher complete response rate than the non-BTZ group: 26.8% vs. 7.2%. More patients in the VMP group achieved ≥very good partial response (VGPR) and ≥PR. In the VMP group, 27 patients (38.0%) received less than 4 cycles. The VMP good adherence group showed a higher 3-year overall survival (OS) rate (70.9%) than the poor adherence group (60.2%, p=0.059). In the multivariate analysis, treatment with ≥4 cycles of VMP was a favorable factor for OS. Conclusion A good adherence to a frontline VMP regimen resulted in favorable long-term survival. Adequate management of AEs will be needed to achieve favorable outcomes in elderly patients with MM.

Which donor is better when a matched donor is not available domestically? Comparison of outcomes of allogeneic stem cell transplantation with haploidentical and international donors in a homogenous ethnic population

A substantial proportion of patients requiring allogeneic stem cell transplantation (alloSCT) do not have a human leukocyte antigen-matched sibling donor and need an alternative donor. In this multicenter retrospective study, we compared the outcomes of 176 patients with myelodysplastic syndrome and acute leukemia undergoing alloSCT from haploidentical (nu202f=u202f121) and international (nu202f=u202f55) donors between 2002 and 2016. For recipients of haploidentical and international donors, the 2-year overall survival rates were 33.4% and 35.3%, respectively (Pu202f=u202f0.347), and relapse-free survival rates were 31.7% and 34.4% (Pu202f=u202f0.264), respectively. In addition, there were no significant differences in the cumulative incidences of acute and chronic graft versus host disease or incidences of infection within 30u202fdays (all Pu202f>u202f0.05). Similarly, there were no significant differences in these measures for acute leukemia patients (nu202f=u202f143; all Pu202f>u202f0.05). A multivariate analysis revealed that the donor type was not an independent prognostic or predictive factor. These data suggest that both haploidentical and international donors are feasible alternative sources for alloSCT when a matched donor is not available domestically.

Impact of consolidation cycles before allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission

Background: The optimal number of high‐dose cytarabine (HDAC) consolidation cycles before allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia is not fully standardized. Patients and Methods: This study evaluated the impact of HDAC consolidation cycles before allogeneic HCT in 194 patients with acute myeloid leukemia in first complete remission between 1998 and 2014. The patients were reclassified into 3 groups—no consolidation (C0, n = 20), 1 consolidation (C1, n = 115), and ≥ 2 consolidations (C2, n = 59)—by pre‐HCT consolidation cycle. Results: The 3‐year relapse‐free survival rates was 45.9%, 66.9%, and 73.3% for the C0, C1, and C2 groups, respectively (P = .064), while the 3‐year overall survival rates were 35.0%, 55.2%, and 67.5%, respectively (P = .106). The cumulative incidence of acute graft‐versus‐host disease (GVHD) was higher in the C2 group (38.7%) than in the C0 (22.2%) or C1 (17.7%) group (P = .018). However, the incidence of chronic GVHD showed no difference between the groups. Multivariate analysis for overall survival revealed the following independent factors: adverse cytogenetic risk (hazard ratio [HR] = 1.84, P = .046), C2 versus C0 (HR = 0.41, P = .037), pre‐HCT status beyond CR1 versus CR1 (HR = 5.78, P < .001), and presence of chronic GVHD (HR = 0.45, P = .004). Conclusion: One or two cycles of HDAC consolidation therapy led to better subsequent HCT outcomes compared to the no–consolidation therapy group.

A phase 4 study of nilotinib in Korean patients with Philadelphia chromosome‐positive chronic myeloid leukemia in chronic phase: ENESTKorea

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR4, and MR4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

Response to hypomethylating agents improves long-term outcomes for lower-risk patients with myelodysplastic syndrome in case-matched cohorts

Predictive factors for initiating hypomethylating agents’ (HMAs) treatment and the survival benefit of HMAs for lower-risk myelodysplastic syndrome (LR-MDS) are still unknown. This study evaluated the factors affecting the use of HMAs and compared long-term outcomes between best supportive care (BSC) and HMA groups after matching baseline clinical factors. Data of 353 patients diagnosed with LR-MDS by International Prognostic Scoring System between October 1992 and July 2013 were retrospectively analyzed. HMAs were administered continuously until a clinical response or progression. HMAs were administered to 243 patients with median 45xa0days (range 0–7078xa0days) after diagnosis, while 110 patients were treated with BSC. HMAs were administered over a median of 5xa0cycles and overall response was achieved in 104 patients (42.8%). The cumulative incidence of HMA treatment increased in higher-risk groups by other risk scoring systems. Three-year overall survival (OS) rate was higher in BSC group (69.1%) than HMA responders (47.4%, pu2009=u20090.065) or HMA non-responders (46.3%, pu2009=u20090.005). Among 162 case-matched cohorts, 3-year OS rates were comparable between the BSC group (67.1%) and HMA responders (58.1%, pu2009=u20090.914), while that of HMA non-responder was low (32.2%, pu2009<u20090.001). In the case-matched cohorts, HMA non-responder were associated with inferior OS rate in the multivariate analysis (hazard ratio 3.01, pu2009=u20090.001). Higher-risk groups by other clinical risk scoring systems among IPSS lower-risk patients showed an increased incidence of using HMAs. The OS rate of HMA responders among case-matched cohorts showed an improved OS rate similar to the BSC group.

Report on outcomes of hypomethylating therapy for analyzing prognostic value of Revised International Prognostic Scoring System for patients with lower-risk myelodysplastic syndromes.

The outcomes for patients with lower-risk myelodysplastic syndromes (LR-MDS) by the International Prognostic Scoring System (IPSS) vary widely. For more precise prognostication, this study evaluates the prognostic value of revised IPSS with the response to hypomethylating therapy (HMT). Using the Korean MDS Working Party database, treatment outcomes for 236 patients with HMT were retrospectively evaluated. The patients were then reclassified into very low/low (VL/L), intermediate (INT), and high (H) risk groups according to IPSS-R. According to the HMT response, the 3-year overall survival (OS) did not differ between the response group (37.9u2009±u20099.1xa0%) and the stable group (52.9u2009±u20096.6xa0%, pu2009=u20090. 782). When reclassifying according to IPSS-R, 42 patients (20.8xa0%) were reclassified into the H risk group. Most of them did not have benefit from continued HMT and progressed to secondary failure. The median OS was 59.0xa0months (range, 40.0–77.9xa0months) for the VL/L risk group, 31xa0months (range, 22.7–439.3xa0months) for the INT risk group, and 20.0xa0months (range, 15.9–24.1xa0months) for the H risk group (pu2009<u20090.001). In the multivariate analysis, the following factors were associated with survival: ageu2009≥u200965 (HRu2009=u20091.515, pu2009=u20090.023), ECOGu2009≥u20092 (HRu2009=u20092.968, pu2009<u20090.001), H risk group according to IPSS-R (HRu2009=u20093.054, pu2009<u20090.001), P/VP cytogenetic risk according to IPSS-R (HRu2009=u20094.912, pu2009=u20090.003), and transformation to AML (HRu2009=u20092.158, pu2009=u20090.002). If IPSS-R reclassifies LR-MDS patients as H risk, these patients should be considered for early allo-HCT, regardless of the current benefits from HMT.